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Review
. 2024 Jun 18;1(3):100015.
doi: 10.1016/j.bvth.2024.100015. eCollection 2024 Sep.

Targeting the P-selectin/PSGL-1 pathway: discovery of disease-modifying therapeutics for disorders of thromboinflammation

Samira Escopy  1 , Elliot L Chaikof  1   2   3
Affiliations
Review

Targeting the P-selectin/PSGL-1 pathway: discovery of disease-modifying therapeutics for disorders of thromboinflammation

Samira Escopy et al. Blood Vessel Thromb Hemost. .

Abstract

P-selectin is a membrane glycoprotein and a member of the selectin family of cell adhesion molecules. It is prestored in α-granules of platelets and Weibel-Palade bodies of endothelial cells and is rapidly expressed on their surfaces upon activation during the course of an inflammatory response. Although a critical component of the innate immune system, the interaction of P-selectin with its cognate ligand, P-selectin glycoprotein ligand 1 (PSGL-1) may mediate maladaptive events central to the pathophysiology of venous thromboembolism, cardiovascular disease, stroke, metabolic syndrome, and sickle cell disease, among other disorders. As a consequence, a growing understanding of the significance of P-selectin and PSGL-1 in human disease has motivated the design of inhibitors that target the P-selectin/PSGL-1 pathway. Herein, we review the development and evaluation of both biologic and small-molecule inhibitors, including preclinical studies and clinical trials that have evaluated therapeutic potential of these agents for a variety of diseases linked to dysregulated inflammatory and thrombotic responses.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Interactions of PSGL-1 with P-selectin. (A) Structure of the P-selectin complex with the PSGL-1 ligand containing tyrosine O-sulfates and the sLex hexasaccharide. The P-selectin surface is color coded according to electrostatic potential (acidic region, blue; basic region, red). In addition, individual sugars in the sLex are color coded (Neu5Ac, purple; Gal and GalNAc, yellow; GlcNAc, blue; and Fuc, red) and the sulfur and oxygen atoms within the sulfate groups are yellow and red, respectively. (B) Interaction map of specific carbohydrate and peptide functional groups with amino acids in the P-selectin binding domain (adapted with permission from Sladek et al, Copyright 2024, American Chemical Society).
Figure 2.
Figure 2.
P-selectin/PSGL-1–mediated leukocyte rolling, adhesion, and transmigration, including a summary of antagonists and current clinical applications.
Figure 3.
Figure 3.
Pan-selectin carbohydrate–based inhibitors designed to mimic the sLeXmoiety of PSGL-1.
Figure 4.
Figure 4.
Small-molecule P-selectin inhibitors in preclinical and early-stage clinical development.
See this image and copyright information in PMC

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